Cold Atmospheric Plasma Elicits Neuroprotection Against Glutamate Excitotoxicity by Activating Cellular Antioxidant Defense

Neuroprotection is critical to rescue injured neural tissues and prevent secondary injuries but current clinical neuroprotection options are alarmingly limited. Following neural injury, reactive oxygen species (ROS) are aberrantly accumulated due to overactivation of glutamate, a major neurotransmitter in the vertebrate nervous system, leading to massive neural cell death. Antioxidant defense of neuronal cells is inherently repressed and poorly compensated by current pharmacological antioxidants. Here, we explore whether cold atmospheric plasma (CAP) with its ROS tuned near their physiological concentrations may be neuroprotective. Using a neural cell model, we show that a single treatment of a helium CAP jet for 4–10 s induces a pulsed elevation by 220% of reduced glutathione, the main ROS-scavenging system in cells, and substantially increase the viability of glutamate-damaged cells, demonstrating neuroprotection against glutamate excitotoxicity. By correlating peroxynitrite, hydrogen peroxide and nitric oxide produced by CAP to literature evidence of their neuroprotective activity when acting alone, we suggest that micromolar-level peroxynitrite and 30–70-µM hydrogen peroxide produced from the CAP jet trigger their known and dose-dependent pathways for activating the cellular antioxidant defense. Collectively, our data show that CAP offers a novel and potentially potent strategy to neuroprotection.